Abstract A024: TIGIT blockade enhances the effect of anti-PD-1 against CD155hi expressing tumors in mouse and human models

Abstract Introduction: TIGIT is an inhibitory receptor expressed by T and NK cells that can negatively impact anti-tumor immunity. TIGIT out-competes an activating receptor, CD226, for a shared receptor ligand, CD155. CD155-TIGIT interactions suppress activation and cytotoxicity, while CD155-CD226 has a stimulatory effect. Phosphorylation and activation of CD226 is also inhibited by PD-1, making the CD155-CD226 signaling axis a unifying and convergent target of both PD-1 and TIGIT. Notably, high tumoral expression of CD155 is predictive of poor performance by anti-PD-1 therapies. Simultaneous blockade of PD-1 and TIGIT may release the inhibitory pressure on CD155-CD226 signaling to enhance effector function of exhausted T (Tex) cells and anti-tumor immunity. Methods: Expression of TIGIT, PD-1, CD226, and CD155 in human tumor biopsies was interrogated by immunohistochemistry and flow cytometry. The impact of tumor cell CD155 expression on TIGIT and PD-1 blockade was assessed in vitro and in vivo using blocking antibodies designed to avoid Fc engagement. CD155-knockout (KO) and CD155-wildtype (WT) MC38 mouse colon adenocarcinoma cells were used to evaluate the effect of anti-TIGIT and anti-PD-1 on in vitro T cell cytotoxicity and in vivo syngeneic tumor growth. TIGIT and PD-1 blockade was assessed using a humanized model where immunocompromised mice were implanted with CD155hi A549 tumor xenografts and engrafted with human peripheral blood mononuclear cells. Results: In human tumor biopsies, PD-1, TIGIT, and CD226 were highly expressed on Tex cell subsets. Histological analyses revealed an inverse relationship between CD155 and CD226 expressions in human tumors that was recapitulated in isogenic CD155-WT and CD155-KO MC38 syngeneic tumors. In vitro, CD155 expression reduced susceptibility of MC38 cells to cytotoxic lymphocyte (CTL) killing, which could be overcome using anti-PD1 or anti-TIGIT and further enhanced in combination. The impact of anti-TIGIT in the CTL killing assay was completely dependent on CD155 expression. Similarly, in vivo TIGIT blockade enhanced tumor control by anti-PD-1 specifically in the CD155-WT setting. In a humanized lung adenocarcinoma xenograft tumor model, PD-1 and TIGIT were highly expressed on engrafted human Tex cells. Significant tumor control associated with activation of precursor Tex cells was observed in animals receiving dual blockade, but not anti-PD-1 alone. Conclusions: While both TIGIT and CD226 can interact with CD155, our studies indicate that the inhibitory CD155-TIGIT interaction dominates in the absence of therapeutic intervention. Furthermore, we interpret the inverse relationship between CD226 and CD155 to be indicative of poor CD226 engagement in CD155low settings and non-productive engagement in CD155hi settings. Blocking TIGIT and PD-1 can tune the immune system toward an activated state, particularly in settings when CD155 is highly expressed, promoting optimal anti-tumor immunity. Citation Format: Hannah E. Meibers, Casey G. Mitchell, Gabrielle L. Reiner, Dana Piovesan, Jas Singh, Saranya Chandrasekar, Yihong Guan, Ritu Kushwaha, Lauren Rocha, Ferdie Soriano, Ruben Flores, Matthew J. Walters, Patrick G. Schweickert, Kelsey E. Sivick. TIGIT blockade enhances the effect of anti-PD-1 against CD155hi expressing tumors in mouse and human models abstract. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A024.